Estrogen deprivation induces hepatic inflammation, Indoleamine-2,3-dioxygenase 1, tryptophan catabolism, and plasma cholesterol

Inflammation is a central mediator linking metabolic dysfunction to severe human disease. Imbalance or loss of ovarian hormone (such as in post-menopausal women) contributes to increased risk of cardiovascular diseases, obesity and others. Here, using ovariectomized (OVX) Long-Evans rats as model for estrogen deprivation, we demonstrate that estrogen deprivation induces hepatic inflammation, activates tryptophan catabolism, systemic inflammation and disrupted cholesterol homeostasis. OVX animals gained more weight and developed an atherogenic plasma profile with increased LDL and total cholesterol and reduced HDL levels compared to intact female animals, which was reversed by estradiol (E2) administration. Ovariectomy results in elevation of hepatic pro-inflammation cytokine (e.g. TNFα, IL6), tryptophan catabolic enzymes (e.g. IDO1, and TDO2) and reduced reverse cholesterol associated gene SR-BI expression and E2- administration also suppressed the ovariectomy-induced hepatic inflammation resulting in reduction of TNFα, IL6, IDO1 and TDO2 while elevation of SR-BI expression. Plasma kynurenine, nitric oxide and lactate were elevated upon ovariectomy suggesting increased system Trp-catabolism, inflammation, each was reversed by estrogen. Targeted LC-MS metabolomics analysis revealed enhanced Trp-to-kynurenine flux, elevated lactate, accumulation of citrate/isocitrate/aconitate, and a reduced α-ketoglutarate/aconitate ratio (~ 0.6) restored by estradiol (~ 3.6). Together, our studies suggest a a link between estrogen signaling and hepatic immune-metabolism via regulation of Trp-catabolism, this open up potential novel signaling pathways for treating cardiometabolic disease and hormonal disorders.